The why and how of sleep-dependent synaptic down-selection

Abstract

Sleep requires that we disconnect from the environment, losing the ability to promptly respond to stimuli. There must be at least one essential function that justifies why we take this risk every day, and that function must depend on the brain being offline. We have proposed that this function is to renormalize synaptic weights after learning has led to a net increase in synaptic strength in many brain circuits. Without this renormalization, synaptic activity would become energetically too expensive and saturation would prevent new learning. There is converging evidence from molecular, electrophysiological, and ultrastructural experiments showing a net increase in synaptic strength after the major wake phase, and a net decline after sleep. The evidence also suggests that sleep-dependent renormalization is a smart process of synaptic down-selection, comprehensive and yet specific, which could explain the many beneficial effects of sleep on cognition. Recently, a key molecular mechanism that allows broad synaptic weakening during sleep was identified. Other mechanisms still being investigated should eventually explain how sleep can weaken most synapses but afford protection to some, including those directly activated by learning. That synaptic down-selection takes place during sleep is by now established; why it should take place during sleep has a plausible explanation; how it happens is still work in progress.

Keywords: Cerebral cortex; Hippocampus; NREM sleep; REM sleep.

Fig. 1.

Homer1a (left) and Arc (right) and their proposed role in synaptic weakening via the endocytosis of AMPA receptors. Sustained neuronal activity, such as during wake, leads to increased mRNA levels of both Homer1a and Arc in the dendritic shaft. Left: Homer1a protein accumulates in the spine in conditions of low noradrenergic activity, such as sleep. Homer1a binds group 1 metabotropic glutamate receptors (Gp1 mGluRs) leading to their constitutive, ligand-independent activation. In cerebellar and hippocampal slices, the activation of Gp1 mGluRs needs to be coupled with depolarization to result in the endocytosis of AMPA receptors (AMPARs), but whether this is also the case during sleep is unknown. If so, neuronal depolarization during REM sleep and/or the UP states of NREM sleep, coupled with low levels of noradrenaline, may be critical for the removal of AMPARs. Right: Arc binds directly AMPARs and promotes their endocytosis. In the hippocampus, Arc-mediated synaptic weakening requires the activation of Gp1 mGluRs, followed by the phosphorylation of the eukaryotic elongation factor 2 (eEF2-P), which in turn promotes the local synthesis of Arc. In visual cortex (V1), Arc targets specifically the less used spines and its accumulation is promoted by high levels of inactive CaMKIIbeta. Whether sleep promotes the accumulation of Arc in the spines is not known.